The cost impact of disease progression to metastatic castration-sensitive prostate cancer

BACKGROUND: Metastatic prostate cancer (PC) is associated with declining survival rates and increased health care expenditure. However, there are few studies quantifying these increased costs. OBJECTIVE: To estimate overall health care resource utilization and costs associated with progression to metastatic disease in Medicare or commercially insured patients with nonmetastatic castration-sensitive PC (nmCSPC) or previously undiagnosed PC. METHODS: In this retrospective, observational cohort study, we used data from the IBM MarketScan Commercial and MarketScan Medicare Supplemental Databases. Included patients were aged 18 years or older, had 2 or more health care claims associated with a diagnosis of PC, and had a diagnosis of metastatic disease (index date) between January 1, 2014, and December 31, 2016. Patients with PC were identified at index as either progressing from a localized disease state (nmCSPC) without evidence of castration resistance (progressors) or de novo metastatic without a prior PC diagnosis. Unadjusted all-cause direct health care costs for the 2-year pre-index period and up to 2 years post-index were summarized. Metastasis-related incremental all-cause direct health care costs were estimated using regression modeling to adjust for patient baseline characteristics, follow-up duration, and possible selection bias. RESULTS: We identified 3,854 patients who met the criteria for CSPC at metastasis: 2,766 Medicare patients (mean age 78.8 ± 7.6 years) and 1,088 commercial patients (mean age 57.6 ± 4.3 years), with de novo patients accounting for 28.9% and 34.5% of the 2 analysis populations, respectively. Mean unadjusted total all-cause health care costs over the 24-month pre-index period among progressors were $52,661 (Medicare) and $43,111 (commercial); those among de novo patients were $39,756 (Medicare) and $22,090 (commercial). Mean unadjusted post-index costs for progressors were $100,331 (Medicare) and $127,374 (commercial) over a mean follow-up duration of 14.63 and 18.41 months, respectively, and $124,538 (Medicare) and $173,408 (commercial) over a mean follow-up duration of 14.14 and 17.29 months for patients with de novo disease. After multivariate adjustment, incremental cost increases due to metastasis in patients with CSPC pre-index were estimated at $104,051 (Medicare) and $93,334 (commercial), assuming data are available for 24 months post-index. Allowing for variation in the postindex observation period, estimates were $71,308 (Medicare) and $82,336 (commercial). Among de novo patients, cost increases due to metastasis were estimated at $180,932 (Medicare) and $215,397 (commercial), assuming all patients have data for 24 months postindex. Allowing for variable follow-up, estimates were $113,253 (Medicare) and $161,714 (commercial). CONCLUSIONS: Development of metastatic CSPC is associated with considerable costs over a 24-month follow-up period. Cost increases are greater for de novo patients than for those who progressed from localized disease.


RESULTS:
We identified 3,854 patients who met the criteria for CSPC at metastasis: 2,766 Medicare patients (mean age 78.8 ± 7.6 years) and 1,088 commercial patients (mean age 57.6 ± 4.3 years), with de novo patients accounting for 28.9% and 34.5% of the 2 analysis populations, respectively. Mean unadjusted total all-cause health care costs over the 24-month pre-index period among progressors were $52,661 (Medicare) and $43,111 (commercial); those among de novo patients were $39,756 (Medicare) and $22,090 (commercial). Mean unadjusted post-index costs for progressors were $100,331 (Medicare) and $127,374 (commercial) over a mean follow-up duration of 14.63 and 18.41 months, respectively, and $124,538 (Medicare) and $173,408 (commercial) over a mean follow-up duration of 14.14 and 17.29 months for patients with de novo disease. After multivariate adjustment, incremental cost increases due to metastasis in patients with CSPC pre-index were estimated at $104,051 (Medicare) and $93,334 (commercial), assuming data are What is already known about this subject • It is estimated that there will be more than 268,000 new cases of prostate cancer (PC) and more than 34,500 deaths from the disease in 2022 in the United States.
• For patients with nonmetastatic castration-sensitive PC (nmCSPC), survival rates decline once the tumor either becomes castration resistant or metastasizes.
• Beyond the impact of metastasis on mortality and patient morbidity, available data suggest that its impact on health care costs is substantial, increasing several-fold following metastasis; however, these data are limited.

What this study adds
• This study uses health care claimsbased data to assess the overall cost impact of metastasis on patients initially diagnosed with nmCSPC or who were metastatic at diagnosis.
• Direct all-cause health care costs in patients with nmCSPC increased between 2-and 4-fold following metastasis, increases that became evident several months before metastasis was diagnosed.
• All-cause health care cost increases were typically higher in patients diagnosed as de novo metastatic.
Prostate cancer (PC) is the most commonly diagnosed cancer and second-leading cause of cancer-related death in men in the United States. 1 Recent estimates suggest there will be in excess of 268,000 new cases of PC and 34,500 deaths from PC in 2022. 1 Approximately 90% of men with an initial diagnosis of PC in the United States undergo primary localized treatment with curative intent. 2,3 For patients with biochemically recurrent, nonmetastatic castration-sensitive PC (nmCSPC), management approaches typically include observation, salvage local therapy (salvage prostatectomy or radiotherapy), and/ or androgen deprivation therapy.2 Survival rates decline, however, with progression to castration-resistant or metastatic disease. 4 Approximately 4% of patients with PC have de novo metastases at diagnosis, 5 and about 80% of metastases in localized PC occur in the bone, 6,7 leading to a 2-and 7-fold increased risk of death. 8,9 Furthermore, patients with bone metastases are predisposed to skeletal-related events (SREs), 8 further increasing the risk of mortality. 9,10 In addition to the increased risks of mortality associated with progression to metastatic PC, several studies suggest the potential for associated increases in health care costs, particularly with metastatic castration-resistant PC (mCRPC). [11][12][13][14] Few studies have assessed the economic impact of nmCSPC to metastatic CSPC (mCSPC) progression, although a study in Medicare patients with localized PC showed an association between metastasis and substantial health care cost increases. These increased costs were evident in the months immediately preceding the diagnosis of metastasis. 15 Our study used insurance claims-based data (Medicare and commercial) to investigate the cost impact of progression to metastatic disease in a large population of patients with CSPC who either progressed from nmCSPC to mCSPC or were metastatic at diagnosis (de novo).

PATIENT SELECTION AND STUDY DESIGN
This retrospective, observational cohort study included patients with CSPC and an initial metastatic progression and those with de novo metastases occurring between January 1, 2014, and December 31, 2016. Administrative claims data from the IBM MarketScan Commercial Database (approximately 41.9 million patient records) and the MarketScan Medicare Supplemental Database (2.5 million Medicareeligible retirees with employer-sponsored Medicare supplemental insurance) were used in this analysis.
For eligibility, patients needed to be aged 18 years or older, have 2 or more health care claims associated with a PC diagnosis ( Patients had to have 2 or more years' continuous preindex enrollment within the same post-index payer type and both medical and prescription drug coverage during the 24 months pre-index. Patients with capitated plans or evidence of a change in payer at any time during the study period were excluded. Patients with one or more prespecified primary cancers pre-index, other than PC, were also excluded. Patients who had potentially progressed to CRPC were excluded, with the following exclusion criteria applied: (1) pre-index history of full/radical orchiectomy; treatment with advanced antiandrogen therapy (enzalutamide, abiraterone, apalutamide), docetaxel, cabazitaxel, sipuleucel-T, or radium-223; (2) use of any luteinizing hormone-releasing hormone/gonadotropin-releasing hormone therapy exceeding 6 months within 2 years before the date of first metastasis; or (3) initiation of bicalutamide or equivalent 30 days or more after the dates of first luteinizing hormone-releasing hormone/gonadotropin-releasing hormone therapy and before initial diagnosis of metastasis. These criteria identified treatments indicated for CRPC according to evidence-based guidelines and availability and are similar to those used elsewhere. 16,17 Patients with de novo mCSPC were identified based on a first PC diagnosis within 30 days before or after the date of first diagnosis of metastasis. Patients with de novo mCSPC available for 24 months post-index. Allowing for variation in the postindex observation period, estimates were $71,308 (Medicare) and $82,336 (commercial). Among de novo patients, cost increases due to metastasis were estimated at $180,932 (Medicare) and $215,397 (commercial), assuming all patients have data for 24 months postindex. Allowing for variable follow-up, estimates were $113,253 (Medicare) and $161,714 (commercial).

CONCLUSIONS:
Development of metastatic CSPC is associated with considerable costs over a 24-month follow-up period. Cost increases are greater for de novo patients than for those who progressed from localized disease.
uses each patient as their own control through incorporation of a fixed effect expressed as: α i is an individual fixed effect for each patient and captures the patient's "baseline" costs reflecting age, sex, comorbidities, and any other patient-specific factor that impacts health care costs and is constant throughout the study period. I t is a binary variable that takes value of 1 if month t has metastasis-related costs, ie, t ∑[−k,23], where −k represents the period prior to metastatic diagnosis to capture potential cost increases due to increased symptoms and diagnostic testing, a period we will refer to subsequently as the "runup" period. γ t is a measure of the average increase in health care expenditures due to metastasis during month t. μ i,t is an error term.
All-cause monthly health care cost patterns prior to index were examined to determine the time of inflection prior to diagnosis when costs began increasing, defined as the point when the subsequent monthly cost estimate exceeded the 95% CI for the mean value of previous months. Using this approach, −k was set at 3 months prior to index for both progressor and de novo samples among Medicare patients, at 4 months for the progressor sample among commercial patients, and at 1 month for the de novo sample among commercial patients.
Consequently, the overall incremental cost of progression consists of incremental costs from both the run-up months −k to −1 and post-index months 0 to 23, after adjusting for health care cost trends and potentially informative censoring.
Coefficients from months −k to 0 were used directly to estimate incremental costs during the run-up period and index. We calculated the average increase in costs after diagnosis based on the assumption that a patient would survive for 24 months or longer, with the coefficients averaged from month 1 through 23, and the adjusted average cost increase, calculated by adjusting the coefficients for loss to follow-up resulting from either mortality or patients leaving/changing their health insurance before determining the average. We assumed that loss to follow-up resulted from mortality, which is a more conservative estimate of costs because of the reduced time frame for cost accrual.
were analyzed as a separate group, reflecting the potential differences in treatment choice and costs associated with this disease.

OUTCOME MEASURES
The focus of this study is all-cause health care costs, derived from the costs arising from inpatient admissions, inpatient services, outpatient services, and outpatient pharmacy settings, paid by the payer (insurer) and the patient (out of pocket).

DATA ANALYSIS
All analyses were stratified by payer type (Medicare or commercial) and patient classification as a progressor (ie, progressed from a localized disease) or de novo metastatic. Data were analyzed using SAS version 9.4. Standard descriptive statistics were used to summarize baseline characteristics and outcomes. To account for variable follow-up duration post-index, costs were summarized as average monthly values over those patients surviving through that month. All costs were adjusted to December 2018 US$ using an inflation adjustment based on the medical component of the consumer price index.
All-cause health care costs were aggregated by month during the pre-index period and up to 2 years following progression (or until patient death or dropout). "Standardized" 30-day months were constructed for each patient moving both backward and forward from the index date. Month 0 for a patient represented the first 30-day period following the index date (inclusive of the index date). Using these standardized months, we accumulated health care costs for each patient by month and summarized these costs descriptively across all patients before and after metastasis ( Figure 1).
We also wanted to capture incremental costs associated with metastasis. Although several approaches are used for incremental cost estimates, we developed a regressionbased model whereby each patient serves as their own control, enabling more accurate per-patient pre-and postmetastasis cost comparisons. The model adjusts for sources of bias not captured in the unadjusted analysis, including variable follow-up duration; inflation-adjusted health care cost increases over time; health care cost increases that occur immediately prior to the diagnosis of metastasis (month −k), potentially due to increased symptoms and diagnostic testing; misclassification bias due to incomplete PC coding; and issues of selection bias associated with patients with more severe disease who may have higher associated costs and higher mortality rates. 18 This model

FIGURE 1
Average Monthly Cost and Patient Count

BASELINE CHARACTERISTICS
Medicare patients were older (78.8 ± 7.6 years) than those in the commercial sample (57.6 ± 4.3) and had a higher mean Charlson Comorbidity Index score (2.0 ± 2.09 vs 0.7 ± 1.21; Table 1). More than 50% of patients had evidence of opioid prescriptions, with schedule II opioids the primary type prescribed (Table 1). Patients in the de novo and progressor samples were similar; however, patients in the de novo sample had more bone metastases and fewer node metastases (Table 1).

Results
Overall    Medicare patients and approximately $700 PPPM for commercially insured patients ( Figure 1). However, in the 3-to 4-month run-up period immediately preceding a diagnosis of metastasis in both the Medicare and commercial samples, monthly health care costs increased (Table 2). Over the 24-month pre-index period, the cumulative unadjusted total mean per-patient costs for the Medicare progressors were $52,661 and $39,756 for the patients with de novo metastases. For commercially insured patients, these costs were lower at $43,111 for the full 24 months for progressors and $22,090 for those with de novo metastases ( Table 2). Pre-index outpatient services costs were the greatest cost component in the Medicare and commercial samples (between 50% and 70% of total costs). Hospitalization costs accounted for between 20% (progressors) and 23%

PATIENT ATTRITION DURING FOLLOW-UP PERIOD
In the Medicare sample, the number of patients declined by 65% (progressors) and 69% (de novo) between index and month 23 (Figure 1). Similar reductions (progressors 48%; de novo 54%) were observed in the commercial sample ( Figure 1).

ALL-CAUSE HEALTH CARE COSTS PRIOR TO METASTASIS
Before the diagnosis of mCSPC and initiation of the runup period, costs for progressors were generally stable at approximately $1,900 and $1,300 per patient per month (PPPM) in the Medicare and commercially insured samples, respectively (Figure 1). Similarly, for patients with de novo mCSPC, mean costs were below $1,300 PPPM for    (Table 2). Relative post-index monthly cost increases were driven by a 7-to 10-fold increase in inpatient costs (hospitalizations) and were greater among patients with de novo metastases (23-fold increase in the commercial group). Outpatient cost increases ranged from approximately 3-fold (Medicare progressors) to approximately 13-fold (commercial patients with de novo metastases). Post-index pharmacy costs also increased but remained at approximately 7% to 8% of total post-index costs (Supplementary Table 1).
Total all-cause health care costs over the 24-month post-index period increased in both groups to $100,331 for progressors and $124,538 for those with de novo metastases in the Medicare group, and to $127,374 for progressors and $173,408 for those with de novo metastases in the commercially insured group. These increases were observed even though the mean post-index follow-up period was substantially shorter than 24 months ( Table 2).
Using our regression-based model without adjustment for pre-assumed mortality, total incremental metastasisrelated health care costs for patients who progressed from nmCSPC to mCSPC (progressors) were $71,308 and $82,336 in the Medicare and commercial samples, respectively. For patients with de novo metastases, costs were higher at $113,253 (Medicare) and $161,714 (commercial; Table 3). Incremental monthly health care costs in the run-up (de novo) in the commercial group and 26% (progressors) and 36% (de novo) in the Medicare group. These costs were typically slightly higher for progressors than for those with de novo metastases. Outpatient pharmacy costs were approximately 13% (for both groups) of total pre-index costs in the Medicare group and 10% (progressors) and 20% (de novo) in the commercial group (Supplementary Table 1).

ALL-CAUSE HEALTH CARE COSTS AFTER METASTATIC DIAGNOSIS
No post-index continuous enrollment criteria were imposed to avoid survival bias. The mean (± SD) duration of followup during the 24-month post-index period for progressors was 14.6 (± 8.9) months and 14.1 (± 8.8) months for de novo patients in the Medicare sample, and 18.4 (± 7.8) months and 17.3 (± 8.0) months in the commercially insured sample, respectively (Table 2), thus making the interpretation of direct comparisons of total costs to the 24-month period prior to diagnosis difficult. The diagnosis of metastasis was associated with a large increase in unadjusted monthly costs at month 0 (index date; Figure 1 and Table 2). Monthly unadjusted costs reduced from this peak during post-index follow-up, although they remained higher than in the preindex period (Figure 1). Unadjusted increases in monthly costs following metastatic diagnosis were $4,263 for progressors and $6,819 for patients with de novo metastases in  We used a regression-based approach to estimate incremental costs associated with a diagnosis of metastasis that incorporated adjustments for trends in health care costs, the changing mix of the population during follow-up, and cost increases prior to diagnosis, with each patient's pre-index health care costs serving as their own control. The cost estimates derived using this regressionbased approach are consistent with those generated using the unadjusted direct cost comparisons also presented. Furthermore, our results show that increased monthly costs become evident several months prior to the diagnosis of metastasis, peaking at diagnosis (index date). Following diagnosis, post-index monthly costs stabilized but were higher than those in the pre-index period.
The model breaks down costs into several components including one that captures baseline cost differences for each patient. The model also includes a time trend for the progression of costs and then estimates "excess costs" for each month during the run-up period and the period following metastasis. Mortality, which was pre-assumed for this analysis as the reason for reduced follow-up, is automatically included by estimating the component for that month based on remaining patients only, adjusting for baseline cost differences. The underlying assumptions of this model are that progression to metastasis is associated with an increase in monthly costs uncorrelated with period (between 1 month and 4 months before diagnosis) were between $5,410 and $7,148. At diagnosis (month 0), incremental health care costs were between $16,751 and $27,470 (Table 3) in patients with de novo metastases and progressors in the Medicare and commercially insured samples. Estimated post-index monthly incremental costs for the patients with de novo metastases (Medicare $7,867; commercial $7,929) were uniformly greater than those for the progressors (Medicare $3,560; commercial $2,744). Adjustment for pre-assumed mortality substantially reduced the total health care cost estimates using this model. In the Medicare population, survival-adjusted incremental costs were 57% higher for patients with de novo metastases than they were for patients with CSPC prior to index, and 90% higher in the commercially insured population (Table 3).

Discussion
In this retrospective claims-based study using data from the IBM MarketScan Commercial and MarketScan Medicare Supplemental Databases, we show that a diagnosis of mCSPC has a substantial cost impact.
There are several challenges associated with frequently used unadjusted measures to assess the incremental cost of disease progression and potential cost off-sets for implementing programs that delay or prevent progression. These challenges include differences in observation periods, selection bias in surviving patients, differences between the index date recorded and the actual date of

TABLE 3
Medicare patients with localized disease who subsequently developed metastases vs matched control patients who had localized disease without metastases. The control patients' costs remained steady at a weighted monthly mean of $2,746. The estimated monthly costs for patients with metastases, however, increased from $2,622 during the 12 months before the diagnosis of metastases to $4,767 at 1 month prior to diagnosis, and peaked at $13,291 in the month that metastases were diagnosed. 15 Thereafter, monthly costs remained significantly higher than in the nonmetastatic controls. 15 In the Medicare patients with mCSPC prior to index in our analysis, we observed a similar increase in monthly all-cause health care costs during the pre-index period, an increase that was evident beginning approximately 4 months pre-index. Costs rose to $5,033 in the month immediately preceding diagnosis, rose further to $19,057 at index, and remained above pre-index levels until the end of the 24-month follow-up. Li et al neither included younger (aged less than 65 years) patients nor examined costs in de novo metastatic patients. Our data show, however, that this finding is observed consistently in patients diagnosed with metastases, whether previously diagnosed with nmCSPC or de novo metastatic, irrespective of age. These findings suggest that patients may have medical issues, elevated prostate-specific antigen levels in the absence of other disease-related symptoms, or disease-related symptoms prior to diagnosis, leading them to seek medical advice and diagnostic procedures in the months before diagnosis. Furthermore, we observed increases in total unadjusted all-cause costs resulting from disease progression, which ranged from a doubling of costs to a 7-fold increase in costs. Wu et al 13 showed that disease progression to mCRPC was associated with increases in unadjusted health care costs between 2012 and 2016 of 5.1-fold for Medicare-insured patients and 6.2-fold for commercially insured patients, confirming the cost burden associated with disease progression. These results suggest that delaying metastasis, either through detection of localized disease prior to de novo manifestation or by initiating or intensifying treatment in patients with nmCSPC who are at most risk of progressing to metastatic disease, may be associated with potential health care cost reductions in addition to improved clinical outcomes. However, it is worth noting that this study is not designed to assess the economic impact or cost-effectiveness of measures used to prevent or delay disease progression and how these may affect the cost estimates presented here.

LIMITATIONS
This study has several limitations, which should be acknowledged. Administrative health care databases are baseline costs and background risk, providing a direct estimate of the increased costs in that month compared with what the costs would have been if patient costs had continued along their individual trend line. Our results using this approach were consistent with the findings from the unadjusted analysis and show that metastasis is associated with a substantial cost burden. Furthermore, the estimates that assume patient survival of 24 months or longer are substantially greater than the survival-adjusted estimates, indicating that careful consideration of the effects of possible mortality is important.
We also compared the costs in patients with a prior diagnosis of CSPC with those with de novo mCSPC in both the Medicare and commercial samples. In this study, we identified 29% of patients in the Medicare analysis population and 34% of patients in the commercial insurance population with de novo mCSPC. For patients with prior CSPC, the diagnosis of metastases represents a failure of their current treatment; however, patients with de novo mCSPC represent a heterogeneous group and includes those with more aggressive and rapidly fatal disease 5,19 requiring more intensive, 5 and potentially more costly, treatment. The increases observed in total all-cause and incremental metastasis-related costs were greater in patients with de novo metastatic disease than in those diagnosed with CSPC prior to index, particularly in the younger patients of the commercially insured sample, and were driven by substantial increases in hospitalizations and outpatient service use. In contrast, the increase in mean monthly costs is relatively low for progressors. This relative incremental cost differential is probably the result of progressors receiving PC-related prior treatment and regular follow-up during the pre-index period. Another likely driver of the increased cost for patients with de novo metastatic disease is the presence of bone metastases, which account for 62% to 75% of metastases in the de novo patients compared with 29% and 48% of metastases in the progressors in our analysis. Bone metastases are indicative of more aggressive disease, with 1-year survival in patients with PC and bone metastases estimated at 35%. 18 In addition to de novo patients requiring more intensive treatment, their increased risk of SREs 10 and the associated additional cost burdens of managing them 8,9 (previously estimated at $20,984 per patient 20 ) lead to further upward pressure on their costs.
There are few published studies assessing the impact of metastasis on health care costs, especially in the mCSPC patient population. However, our results are consistent with previously published findings. Li et al 15 used a longitudinal mixed effects regression model over a 12-month post-index period to estimate the monthly costs for potential cost benefits, arising from improved management and diagnosis, to both patients and payers.

DISCLOSURES
Q.-D. Trinh received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical. L. Passos Chaves, Q. Feng, J. Zhu, and T. Abbott are employees of Astellas Pharma Global Development, Inc. R. Sandin is an employee of, and holds stock in, Pfizer AB. This study was funded by Astellas Pharma Inc. (Northbrook, IL) and Pfizer Inc., the codevelopers of enzalutamide. Astellas Pharma Inc. was involved in the study design, data collection, analysis, interpretation of data, and decision to present these results.
both cases impacting the incremental costs estimates. In addition, there was an attrition rate across the analysis groups of between 48% and 69%, a rate that was highest in the Medicare group (65%-69%). We have assumed that this attrition is the result of mortality, which in unadjusted models could lead to selection bias, as patients with more severe illness and potentially higher costs may have a higher mortality rate. However, our adjusted multivariate model addresses this selection bias by including an adjustment for mortality. Finally, the costs described here apply only to an insured population with noncapitated employer-sponsored health insurance coverage and may not represent the wider population of patients with PC in the United States.

Conclusions
Our study shows that all-cause health care costs in patients with nmCSPC increase between 2-and 4-fold following metastasis, with increases evident several months before metastatic diagnosis. All-cause health care cost increases were typically higher in patients diagnosed as de novo metastatic than in patients who progressed from nonmetastatic disease, a finding that could have potential implications for screening and treatment algorithms. Furthermore, in addition to the clinical benefits associated with the prevention of, or reduction in the incidence of, metastasis, our data suggest that cost savings may be achieved, though these would have to be offset against higher costs from increased screening and/or intensified treatment programs. Our use of regression-based modeling to adjust for some of the limitations of existing health care cost estimates provides additional insight into these costs and will help inform future treatment choices by providing an overview of associated with several inherent limitations including lack of data on patient race, socioeconomic status, laboratory measures, and clinical trial participation, as well as incomplete or inaccurate diagnosis codes, a limitation that may impact the applicability of results to a wider population. Additional unmeasured variables may introduce an endogeneity bias that cannot be adequately controlled. Although we included an assessment of specific cost components in this analysis, no specific data on the types of services being used (eg, diagnostic procedures) were available. This could be a potential subject for future study, as would the effects of treatment with novel hormonal therapies (NHTs) in patients with mCSPC, which were not approved to treat mCSPC in the period covered by this analysis. It is worth noting, however, that although NHTs have now been approved for use in mCSPC, recent evidence suggests that, despite improved outcomes with NHTs vs androgen deprivation therapy alone, few patients with mCSPC receive these therapies. 17 Furthermore, the absence of a diagnosis code within the outpatient pharmacy claims meant that the identification of potentially disease-related medications and associated costs was limited to opioids and SREs. To obtain the full 24 months' data prior to the index date, patients who changed insurance type during the analysis period were excluded. This meant that the commercial patient population excluded patients aged greater than 63 years, whereas the Medicare patient population excluded those aged less than 67 years at the time of first metastasis. By excluding older patients from the commercial group, costs in the pre-index period may have been underestimated, whereas the exclusion of younger patients in the Medicare sample may have led to the overestimation of pre-index costs, in